Lower urinary tract disease is a generic term for subjective or objective abnormality during a process from storage of urine (urinary storage) to excretion of urine (urination), and is classified into urinary storage disturbance (urinary incontinence, voiding frequency etc.), and voiding disturbance (voiding difficulty, micturition pain, urinary tract obstruction etc.). Although lower urinary tract disease is also observed in young people, with progression of an aging society, lower urinary tract disease of the elderly, particularly, voiding disturbance, inter alia, voiding difficulty accompanied with benign prostatic hyperplasia has become a great social problem recently.
Urination is controlled by a peripheral nervous system composed of parasympathetic nerve such as pelvic nerve, sympathetic nerve such as hypogastric nerve and somatic nerve such as pudic nerve under control of micturition center, and it is suggested that various neurotransmitters (e.g. acetylcholine, noradrenaline, ATP, substance P, neuropeptide Y etc.) are involved in micturition.
As a therapeutic agent for voiding disturbance, in particular, voiding difficulty, a medicine for augmenting a contractile force of bladder muscle (detrusor muscle), or a medicine for relaxing urethral smooth muscle and alleviating urethra resistance is used. As a medicine which acts on bladder muscle and augments its contractile force, a choline agonist such as bethanechol, and acetylcholinesterase inhibitor such as distigmine are used. However, for example, bethanechol constricts also bladder muscle at a urinary storage stage and damages urinary storage function of bladder and, at the same time, has side effects such as lacrimation, sweating, gastrointestinal disorder, and bellyache and, therefore, is contraindicated to pregnant woman, digestive ulcer, organic ileus, asthma, and hyperthyroidism. Satisfactory medicines have not been found out yet.
As an acetylcholinesterase inhibitor having augmenting action of a bladder muscle contractile force, for example, distigmine and neostigmine are known. Since an acetylcholinesterase inhibitor potentiates an action of acetylcholine which is released from a pelvic nerve terminal during voiding, it augments the contraction of a bladder muscle during voiding, and is an excellent drug in view of physiological mechanism of voiding. However, for example, while distigmine contracts a bladder muscle, it contracts urethral sphincter muscle due to its strong nicotinic action and increases urethral resistance, resulting in a deteriorated voiding efficiency and insufficient clinical effect. Further, a risk of high pressure voiding is pointed out. In addition, since neostigmine has short-lasting action, it is not used in therapy (see, for example, Non-Patent Document 1).
As a medicine for relaxing urethra smooth muscle and alleviating urethral resistance, an α1 receptor antagonist such as tamsulosin, prazosin, alfuzosin, naftopidil and urapidil is used, and it is reported that the antagonist has the effect of improving subjective symptom such as residual urine feeling and nocturia. However, the antagonist has an antihypertensive effect such as orthostatic hypotension as side effect, and an attention must be paid to therapy.
On the other hand, Patent Document 1 discloses an acetylcholinesterase inhibitor used as a preventive or a therapeutic agent for voiding disturbance (voiding difficulty), and it is reported that a urine flow rate is considerably improved by using a combination of an α1 receptor antagonist and an acetylcholinesterase inhibitor. However, concomitant use of two agents is not satisfactory in terms of therapy and therapeutic economy considering the burden of a patient to which agents are administered and the trouble of compounding and the like. In addition, a possibility that exacerbation of side effect and death accident might occur by drug interaction due to concomitant use is pointed out, and a sufficient attention must be paid thereto.
In addition, amine compound having various pharmacological activities are reported as follows:
(1) Patent Document 2 discloses, for example, compounds of the following formulas, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(2) Patent Document 3 discloses, for example, a compound of the following formula, as a σ ligand used as a therapeutic for central nervous disease.
(3) Patent Document 4 discloses, for example, a compound of the following formula, as a synthetic intermediate for a sulfur-containing compound.
(4) Patent Document 5 discloses, for example, a compound of the following formula, as a derivative of 4-aminobutyrophenones used as a tranquilizer.
(5) Patent Document 6 discloses, for example, a compound of the following formula, as a compound used as an antibacterial agent.
(6) Patent Document 7 discloses, for example, a compound of the following formula, as a 5-HT4 receptor ligand.
(7) Non-Patent Document 2 discloses, for example, a compound of the following formula, as a 5-HT4 receptor antagonist.
(8) Patent Document 8 discloses, for example, a compound of the following formula, as a compound having thermogenesis promoting activity and anti-obesity activity.
(9) Patent Document 9 discloses, for example, a compound of the following formula, as an acetylcholinesterase inhibitor.
(10) Patent Document 10 discloses, for example, a compound of the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(11) Patent Document 11 discloses, for example, a compound of the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(12) Patent Document 12 discloses, for example, a compound of the following formula, as a compound used as a depressor or an antiarrhythmic.
(13) Patent Document 13 discloses, for example, a compound of the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(14) Patent Document 14 discloses, for example, a compound of the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(15) Patent Document 15 discloses, for example, a compound having the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.
(16) Patent Document 16 discloses, for example, a compound having the following formula, as an acetylcholinesterase inhibitor used as a therapeutic for Alzheimer-type dementia.

However, a compound having both of an acetylcholinesterase inhibitory activity and an α1 receptor antagonistic activity and effect thereof as a preventive or a therapeutic agent for voiding disturbance (voiding difficulty) have not been reported, suggested or disclosed at all until now.
In addition, as a method for assessing a therapeutic agent for voiding disturbance accompanied with benign prostatic hyperplasia in vivo, for example, Non-Patent Documents 3 to 5 disclose a method for measuring reduction of intraurethral pressure due to drug administration using an animal loaded with phenylephrine. However, this method is a procedure for observing the change of intraurethral pressure, and can not measure a urine flow at that time.
On the other hand, as a method for assessing an intraurethral (intravesical) pressure and an urine flow at the same time, Pressure Flow Study is known. For example, there is a description regarding application of Pressure Flow Study to a human in Non-Patent Document 6. In addition, Non-Patent Documents 7 to 9 disclose Pressure Flow Study in an experimental animal. However, these Documents do not disclose a case using an animal model loaded with phenylephrine, and assessment of a therapeutic agent for voiding disturbance accompanied with benign prostatic hyperplasia can not be properly carried out.
[Non-Patent Document 1]
“Diagnosis and Therapy of Neurogenic Bladder” 2nd edition, Takamichi Hattori, Kosaku Yasuda, Igakushoin p. 105–106, p. 139
[Non-Patent Document 2]
Bioorganic and Medicinal Chemistry Letters, 1995, vol. 5, P. 2119–2122
[Non-Patent Document 3]
The Journal of Pharmacology and Experimental Therapeutics, 1999, vol. 291, p. 81
[Non-Patent Document 4]
The Journal of Pharmacology and Experimental Therapeutics, 2002. vol. 300, p. 487
[Non-Patent Document 5]
The Journal of Pharmacology and Experimental Therapeutics, 2002. vol. 300, p. 495
[Non-Patent Document 6]
The mechanics and hydrodynamics of the lower urinary tract, Medical physical handbooks. Bristol, 1980
[Non-Patent Document 7]
The Journal of Urology, 1995, vol. 154, p. 580
[Non-Patent Document 8]
American Journal of Physiology, 1995, vol. 269, p. 98
[Non-Patent Document 9]
Neurourology and Urodynamics, 1996, vol. 15, p. 513
[Patent Document 1]
EP-A 1118322
[Patent Document 2]
EP-A 562832
[Patent Document 3]
WO 95/131
[Patent Document 4]
GB 1489080
[Patent Document 5]
U.S. Pat. No. 4,001,312
[Patent Document 6]
WO 01/25227
[Patent Document 7]
WO 94/27965
[Patent Document 8]
WO 98/46590
[Patent Document 9]
JP-A 6–263733
[Patent Document 10]
EP-A 487071
[Patent Document 11]
EP-A 378207
[Patent Document 12]
EP-A 30044
[Patent Document 13]
EP-A 560235
[Patent Document 14]
EP-A 567090
[-Patent Document 15]
EP-A 607864
[Patent Document 16]
EP-A 655451